Microglial activation in the motor cortex mediated NLRP3-related neuroinflammation and neuronal damage following spinal cord injury

Abstract

Spinal cord injury (SCI) is a traumatic event that can lead to neurodegeneration. Neuronal damage in the primary motor cortex (M1) can hinder motor function recovery after SCI. However, the exact mechanisms involved in neuronal damage after SCI remain incompletely understood. In this study, we found that microglia were activated in M1 after SCI, which triggered Nod-like receptor protein 3 (NLRP3) related chronic neuroinflammation and neuronal damage in vivo. Meanwhile, treatment with the microglia inhibitor minocycline reduced inflammation-induced neuronal damage in M1, protected the integrity of the motor conduction pathway, and promoted motor function recovery. Furthermore, we simulated chronic inflammation in M1 after SCI by culturing the primary neurons in primary microglia-conditioned medium, and observed that the injury to the primary neurons also occurred in vitro; however, as observed in vivo, these effects could be mitigated by minocycline treatment. Our results indicated that microglial activation in M1 mediates NLRP3-related neuroinflammation and causes the injury to M1 neurons, thereby impairing the integrity of the motor conduction pathway and inhibiting motor function recovery. These findings might contribute to the identification of novel therapeutic strategies for SCI.

An emerging role of inflammasomes in spinal cord injury and spinal cord tumor

“…demonstrated that NLRP3-related inflammation in motor neurons was induced by microglial activation in the motor cortex, which impaired motor function recovery after SCI. Minocycline inhibited microglia activation, thus reducing NLRP3-related inflammation and promoting functional recovery after SCI ( 53 ). More recently, an increasing number of chemicals and molecules, such as trehalose ( 54 ), cannabinoid receptor-2 ( 55 ), zinc ( 56 ), melatonin ( 57 ), and dopamine ( 58 ), have been found to improve functional recovery after SCI by targeting NLRP3 inflammasome directly or indirectly.…”

“…Hu et al. demonstrated that microglial activation triggered NLRP3-related inflammation in the motor cortex after SCI ( 53 ). Liu et al.…”

“…Zendedel et al found that ASC, the inflammasome adaptor protein, was predominantly expressed in microglia after SCI (46). Hu et al demonstrated that microglial activation triggered NLRP3-related inflammation in the motor cortex after SCI (53). Liu et al found that oxidation protein products, which served as biomarkers of oxidative stress-triggered inflammatory response after SCI, participated in NLRP3-mediated pyroptosis (67).…”

Role of NLRP3 Inflammasome in Post-Spinal-Cord-Injury Anxiety and Depression: Molecular Mechanisms and Therapeutic Implications

“…It has been shown that ASC is predominantly expressed in microglia following SCI . Moreover, the activation of microglia in the motor cortex has been correlated with NLRP3-mediated neuroinflammation and neuronal degeneration subsequent to SCI . Following the onset of SCI, astrocytes infiltrate the damaged tissue, release inflammatory mediators, and contribute to the development of fibrosis .…”

“…79 Moreover, the activation of microglia in the motor cortex has been correlated with NLRP3-mediated neuroinflammation and neuronal degeneration subsequent to SCI. 156 Following the onset of SCI, astrocytes infiltrate the damaged tissue, release inflammatory mediators, and contribute to the development of fibrosis. 157 The progression of secondary damage in the spinal cord is significantly influenced by the activation of ASC-dependent inflammasomes, specifically in resident cells such as astrocytes and microgelia.…”